This invention relates to substituted urea derivatives useful in the treatment of inflammation in joints, central nervous system, gastorintestinal tract, endocardium, pericardium, lung, eyes, ears, skin and urogenital system. More particularly, this invention relates to aryl and heteroaryl substituted sulfonyl ureas that are useful inhibitors of interleukin-1.alpha. and interleukin-1.beta. processing and release.
IL-1's status as an important mediator of inflammation is based on many studies demonstrating this cytokine's proinflammatory activity. In vivo these effects are manifest as stimulation of cartilage resorption, induction of leukocyte recruitment and the acute phase response, and the production of fever and a shock like state. The changes mediated by IL-1 binding to its receptor include regulation of adhesion molecules and chemokines, stimulation of metalloprotease synthesis, increased synthesis of cyclooxygenase-2 and phospholipase A2 thus increasing prostaglandin production, the induction of nitric oxide synthase thus increasing nitric oxide production and stimulation of IL-6 synthesis resulting in changes in the synthesis of acute phase proteins. Two distinct forms of IL-1 (IL-1.alpha. and IL-1.beta.) are produced by monocytes and macrophages in response to inflammatory stimuli.
The initial translation product of human IL-1.beta. is a 31 kDa polypeptide that is incompetent to bind to IL-1 receptors on target cells. To promote its biological activity, proIL-1.beta. first must be cleaved by a thiol protease to generate a 17 kDa mature polypeptide species. This protease, interleukin-1 convertase (ICE), is a member of a novel family of cytosolic proteases that require an aspartic acid residue at the P1 subsite of their substrates. In contrast to proIL-1.beta., 31 kDa proIL-1.alpha. is competent to bind to IL-1 receptors; nonetheless, this cytokine also is processed to a 17 kDa species by a protease distinct from ICE.
Both forms of IL-1 are synthesized without signal sequences and, as a result, these cytokines accumulate within the cytoplasm of LPS activated monocytes and macrophages. Thus, unlike the majority of secreted cytokines that are processed via the traditional secretory apparatus of the cell involving the endoplasmic reticulum and Golgi apparatus, IL-1 must gain access to the extracellular compartment via a novel secretory pathway. The mechanistic elements of this pathway remain unknown. Recent studies, however, have demonstrated that synthesis of IL-1.beta. is not coupled to its secretion. Agents that serve as a stimulus to promote IL-1.beta. posttranslational processing (both proteolytic clevage by ICE and release of the mature 17 kDa species) include ATP, cytolytic T-cells, and ionophores such as nigericin. Importantly, LPS-activated murine peritoneal macrophages in vivo also require a secondary stimulus to promote efficient release of mature IL-1.beta., and ATP was demonstrated to serve in this capacity. Thus, IL-1.beta. production is highly regulated both in vitro and in vivo by requiring separate stimuli to promote transcription, translation, and posttranslational maturation/release.
Therapeutic approaches that seek to inhibit ICE as a means to regulate production of IL-1 are likely to be limited because ICE inhibitors: 1) do not block release of proIL-1.beta. which could be processed extracellularly by other proteases to generate a mature biologically active cytokine species, and 2) do not decrease production of IL-1.alpha. by activated monocytes/macrophages. Therefore, a therapeutic approach that prevents activation of the posttranslational processing and release of IL-1 is likely to provide efficacy superior to that of an ICE inhibitor by blocking externalization of both cytokine species.
Mammalian cells capable of producing IL-1 include, but are not limited to, karatinocytes, endothelial cells, mesangial cells, thymic epithelial cells, dermal fibroblasts, chondrocytes, astrocytes, glioma cells, mononuclear phagocytes, granulocytes, T and B lymphocytes and NK cells.
The activities of interleukin-1 are many. Subcutaneous injection of IL-1 leads to fever, sleepiness, anorexia, generalized myalgias, arthralgias, headache, and, on increasing exposure, hypotension. Margination of neutrophils and maximal extravascular infiltration of the polymorphonuclear leukocytes (PMN) is also observed. IL-1 also stimulates chondrocytes to release matrix metalloproteases, resulting in the degredation of cartilage matrix.
Accordingly, disease states in which the IL-1 processing and release inhibitors of Formula 1 may be useful as therapeutic agents include, but are not limited to, infectious diseases where active infection exists at any body site, such as meningitis and salpingitis; complication of infections including septic shock, disseminated intravascular coagulation, and/or adult respiratory distress syndrome; acute or chronic inflammation due to antigen, antibody and/or complement deposition; inflammatory conditions including arthritis, cholangitis, colitis, encephalitis, endocarditis, glomerulonephritis, hepatitis, myocarditis, pancreatitis, pericarditis, reperfusion injury and vasculitis. Immune-based diseases which may be responsive to IL-1 processing and release inhibitors of Formula 1 include but are not limited to conditions involving T-cells and/or macrophages such as acute and delayed hypersensitivity, graft rejection, and graft-versus-host disease; auto-immune diseases including Type 1 diabetes mellitus and multiple sclerosis. IL-1processing and release inhibitors of Formula 1 may also be useful in the treatment of bone and cartilage resorption as well as diseases resulting in excessing deposition of extracellular matrix. Such diseases include periodonate diseases, interstitial pulmonary fibrosis, cirrhosis, systemic sclerosis and keloid formation. IL-1 processing and release inhibitors of Formula 1 may also be useful in treatment of certain tumors which produce IL-1 as an autocrin growth factor and in preventing the cachexia associated with certain tumors. IL-1 processing and release inhibitors of Formula 1 may also be useful in the treatment of neuronal diseases with an inflammatory component, including, but not limited to Alzheimers disease, depression and percussion injury. IL-1 processing and release inhibitors may also be useful in treating cardiovascular diseases in which recruitment of monocytes into the subendothelial space plays a role, such as the development of atherosclerotic placques.